Project Summary There is consistent evidence linking socioeconomic status (SES) to Alzheimer?s disease and related dementia (ADRD). Much of the existing research simply quantifies social inequalities in ADRD rather than seek to explain them. Research on other chronic diseases and mortality using a social epidemiological framework has examined the role of multiple risk and protective factors. Our overarching aim is use this approach to identify social, behavioral, and biologic factors actors that mediate the association between socioeconomic status and ADRD. Two features of our project are important. One, we use the lifecourse approach due to the long latent phase of ADRD which can result in modification of risk factors in the preclinical phase of disease. We use three measures of SES (parental SES, own education, adult SES), and risk factors at age 50 and 65 years for mediation analysis. Two, SES is also considered to be a marker of cognitive reserve, in that it modifies the association between neuropathology with clinical dementia. Whether the association of major risk factors of ADRD is also modified by SES is unknown. Our proposal is based on the Whitehall study (N=10,308), a unique resource to study ADRD due to availability of data on multiple risk factors; assessed every 4/5 years over 30 years (1985 to 2016). In three interrelated aims we seek to AIM 1. Identify mid- and late-life risk factors for cognitive impairment and ADRD and test the reserve hypothesis (effect modification). We hypothesize that for midlife risk factors that have a robust association with ADRD, there will be significant effect modification due to the clustering of risk factors with socioeconomic disadvantage. AIM 2. Examine the extent to which risk factors mediate the association of socioeconomic factors with cognitive impairment and ADRD using a causal framework that allows effect modification (moderated mediation). We hypothesize that a considerable proportion of the excess risk will be explained by ?indirect? effects, i.e. via the risk factors considered in the model. AIM 3. Examine whether socioeconomic factors modify a) associations of risk factors with neuroimaging measures, and b) the association of neuroimaging measures with ADRD and cognitive impairment in the Whitehall MRI sub-study.. Increasing longevity across the world will exacerbate the societal and economic impact of ADRD in the coming years. The etiology of ADRD is complex and multifactorial; many risk factors are potentially modifiable and understanding their role is important in the drive to reduce inequalities in ADRD. This project is low risk and highly feasible due to data already collected over 30 years in the Whitehall study. Our comprehensive approach aims to identify specific risk factors that underlie socioeconomic differences in risk of ADRD so that they can be targeted via prevention strategies to reduce inequalities.